Level 1: Likely reliable evidence

The Action in Diabetes and Vascular Disease: Preterax and Diamicron MR Controlled Evaluation (ADVANCE) trial compared a combination of perindopril (an ACE inhibitor) 2 mg plus indapamide (Preterax) 0.625 mg (a diuretic) with placebo (Lancet. 2007;370:829-840). Study participants were older than 55 years with type 2 diabetes (diagnosed after age 30 years) and a history of or risk factors for cardiovascular disease. After a six-week run-in period, 11,140 patients who adhered to and tolerated the study drug were randomized to a combination tablet vs. placebo for mean follow-up 4.3 years (range one month to 5.6 years); the dose was doubled after three months.

Perindopril/indapamide was associated with decreased all-cause and cardiovascular mortality. It was also associated with reduced total coronary events, defined as a major macrovascular event (cardiovascular death, non-fatal MI, non-fatal stroke) or hospitalization for unstable angina, coronary revascularization, or silent MI.

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There were no significant differences in rates of major microvascular events (new or worsening nephropathy [macroalbuminuria, doubling of serum creatinine to ≥2.26 mg/dL, renal replacement therapy, or death from renal disease] or retinopathy [proliferative retinopathy, macular edema, diabetes-related blindness, or retinal photocoagulation therapy]). Comparing perindopril/indapamide vs. placebo, 3.3% vs. 3.9% had new or worsening nephropathy and 19.6% vs. 23.6% had new microalbuminuria.

There were no differences in rates of treatment adherence comparing perindopril/indapamide vs. placebo; 3.3% vs. 1.3% discontinued due to cough, and 1.2% vs. 0.4% discontinued due to hypotension or dizziness. At the time of this summary, Preterax was not an FDA-approved drug.